Glucocorticoids are commonly used for the treatment of rheumatoid arthritis (RA), but, although these are one of the most effective medications to control symptoms and prevent structural progression, their associated potential toxicity requires care and vigilance. The authors of a review published in Rheumatic & Musculoskeletal Diseases presented the current status of glucocorticoids use in RA, and discussed future research avenues.¹

Glucocorticoids have had an important role in the management of RA in past decades, as these medications have both anti-inflammatory and immunosuppressive effects (eg, inhibition of prostaglandin and leukotriene synthesis, interleukin-1 secretion).²

Glucocorticoids are used in patients with RA until disease-modifying antirheumatic drugs (DMARDs) become effective. While very effective for rapid symptomatic relief, adverse events associated with long-term use should be taken into account with dose reductions and treatment cessation occurring as early as possible.¹

In 2019, the European League Against Rheumatism updated its guidelines for the management of RA and the use of biologic DMARD, recommending that short-term glucocorticoids be considered when initiating or changing conventional synthetic DMARDs. Glucocorticoids may be administered via routes (eg, oral, intramuscular, intravenous, and intraarticular), and should be tapered as rapidly as clinically feasible.³

In 2015, the American College of Rheumatology acknowledged the potential benefits of glucocorticoid therapy as a short-term option to bridge patients initiating DMARDs. However, as there are limited data on the safety of long-term glucocorticoid treatment, these medications should be used at the lowest possible dose and for the shortest possible duration to provide the best benefit to risk ratio for patient.⁴

There are difference between the European and the US recommendations regarding the definition of low dose and short-term treatment (European recommendations: daily prednisone dose of 7.5 mg and use of glucocorticoids for up to 6 months; US recommendations: daily dose <10 mg; glucocorticoid tapering within 3 months.^{3, 4}

Current Practice

Glucocorticoid prescribing for RA was found to vary greatly among rheumatologist, and provider preference to be one of the most important factors in predicting long-term glucocorticoid use.⁵

In a study in which the use of glucocorticoids was assessed among Australian patients with RA, glucocorticoid use was found to have decreased in recent years, with a concomitant increase in glucocorticoid cessation.⁶ More specifically, in the period between September 2001 and March 2005, 55% of patients with RA were treated with glucocorticoids compared with 47% between March 2005 and September 2008, 42% between March 2012 and October 2015, and 39% between March 2012 and October 2015.

Glucocorticoid Efficacy

Data on the efficacy of glucocorticoids are mainly based on studies in which treatments of patients with early vs established RA are assessed. In addition, combinations of glucocorticoids and conventional synthetic DMARDs vs in combination with biologic or targeted synthetic DMARDs, are generally assessed.¹

Although results from several studies support the effectiveness of short-term glucocorticoids in reducing disease activity in patients with RA, data on the medium and long-term effects of glucocorticoids are limited.¹ Glucocorticoids are not recommended as monotherapy for patients with RA and should always be used in combination with DMARDs.¹

Treatment with glucocorticoids in combination with conventional synthetic DMARDs may significantly reduce radiographic progression of RA. In the CAMERA-II study, treatment of patients with early RA with a combination of methotrexate and low-dose prednisone for a period of 2 years after diagnosis was associated with reduced, erosive joint damage progression, disease activity, physical disability, and need to add for cyclosporine or biologic agent.⁷

Glucocorticoid Use Strategies

Bridging therapy: Glucocorticoids may be used as bridging therapy between the initiation of conventional synthetic and biologic DMARDs and occurrence of therapeutic effect of these slower-acting agents. One of the landmark studies on glucocorticoid use in early rheumatoid arthritis is The Combination Therapy Trial in Early Rheumatoid Arthritis (COBRA) study in which treatment regimens with initially higher-dose oral prednisone (60 mg/day, tapering to 7.5 mg/day by week 6 and then stopping after week 12) in combination with conventional DMARDs were found to substantially inhibit the progression of radiographic joint damage.⁸ In an open-label study, lower initial doses of glucocorticoids (ie, 30 mg prednisone daily) were found to have comparable efficacy to the higher dose used in the COBRA study.⁹ The benefit of the addition of glucocorticoids to biologic and targeted synthetic DMARDs may be limited due to their fast onset of action.¹

Flare therapy: While adding glucocorticoids to ongoing treatment with conventional synthetic DMARDs may improve outcomes, data on this topic are limited.¹

Maintenance Therapy: Current recommendations stipulate that glucocorticoids be used as a short-term option for RA. However, many patients receive low-dose glucocorticoids for months to years.¹

Glucocorticoid Safety

Glucocorticoid treatment may be associated with adverse events which are duration- and dose-dependent. However, treatment with glucocorticoids at a low-to-medium dose may cause significant adverse events.¹

Most frequent adverse events include increased risk for cardiovascular diseases, infections, gastrointestinal diseases, psychological disorders, endocrine dysfunction, skin problems, and musculoskeletal and ophthalmologic diseases.¹

Treatment with glucocorticoids was found to be associated with increased mortality rates in patients with RA and comorbid diabetes mellitus, compared with patients with RA only.¹⁰

Future Research

Additional studies to evaluate the use of glucocorticoids for the treatment of RA are required (eg, to determine medium- and long-term benefits of glucocorticoids optimal treatment duration). As most data on the use of glucocorticoids as bridging therapy are based on a combined treatment with conventional synthetic DMARDs, more studies are needed to examine the use of glucocorticoids after initiation of a biologic or targeted synthetic DMARD. Data on the use of glucocorticoids to treat for disease flares are scarce and this topic requires further investigation. Finally, studies evaluating the toxicity of glucocorticoids may identify individual factors that affect the risk for treatment-related adverse events.

In conclusion, while glucocorticoids play an important role in patients with RA, potential associated harm and toxicity should be acknowledged. “[F]urther guideline updates will need to address specific conditions and circumstances for which [glucocorticoids] should be prescribed in order to improve the balance between efficacy and long-term safety,” noted the review authors.¹

References

Hua C, Buttgereit F, Combe B. Glucocorticoids in rheumatoid arthritis: current status and future studies. RMD Open. 2020 Jan;6(1):e000536. doi: 10.1136/rmdopen-2017-000536
Buttgereit F, Straub RH, Wehling M, Burmester GR. Glucocorticoids in the treatment of rheumatic diseases: an update on the mechanisms of action. Arthritis Rheum. 2004 Nov;50(11):3408-17. doi: 10.1002/art.20583
Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020 Jun;79(6):685-699. doi: 10.1136/annrheumdis-2019-216655
Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2016 Jan;68(1):1-25. doi: 10.1002/acr.22783
George MD, Baker JF, Wallace B, et al. Variability in glucocorticoid prescribing for rheumatoid arthritis and the influence of provider preference on long-term use. Arthritis Care Res (Hoboken). 2020 Jul 23. doi: 10.1002/acr.24382
Black RJ, Lester S, Buchbinder R, et al. Factors associated with oral glucocorticoid use in patients with rheumatoid arthritis: a drug use study from a prospective national biologics registry. Arthritis Res Ther. 2017 Nov 15;19(1):253. doi: 10.1186/s13075-017-1461-3
Black RJ, Lester S, Buchbinder R, et al. Factors associated with oral glucocorticoid use in patients with rheumatoid arthritis: a drug use study from a prospective national biologics registry. Arthritis Res Ther. 2017 Nov 15;19(1):253. doi: 10.1186/s13075-017-1461-3.
Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med. 2007 Mar 20;146(6):406-15. doi: 10.7326/0003-4819-146-6-200703200-00005
Verschueren P, De Cock D, Corluy L, et al. Effectiveness of methotrexate with step-down glucocorticoid remission induction (COBRA Slim) versus other intensive treatment strategies for early rheumatoid arthritis in a treat-to-target approach: 1-year results of CareRA, a randomised pragmatic open-label superiority trial. Ann Rheum Dis. 2017 Mar;76(3):511-520. doi: 10.1136/annrheumdis-2016-209212
Costello RE, Marsden A, Movahedi M, et al. The effect of glucocorticoid therapy on mortality in patients with rheumatoid arthritis and concomitant type II diabetes: a retrospective cohort study. BMC Rheumatol. 2020 Feb 19;4:4. doi: 10.1186/s41927-019-0105-4

Considerations for the Use of Glucocorticoids in Rheumatoid Arthritis